15-Methyl and 15-ethyl prostaglandin F{HD 2{331 {0 {B analogs

ABSTRACT

Prostaglandin F2 -type compounds with a methyl or an ethyl substituent at C-15. These are useful for the same pharmacological purposes as the unsubstituted prostaglandins.

United States Patent Bundy Sept. 9, 1975 [54] IS-IVIETHYL AND 15-ETHYL [58] Field of Search 260/468 D, 514 D PROSTAGLANDIN F ANALOGS [75] Inventor: Gordon L. Bundy, Portage, Mich. [561 References C'ted [73] Assignee: The Upjohn Company, Kalamazoo, UNITED STATES PATENTS Mich 3,296,091 1/1967 Beal 195/30 3,514,383 5/1970 Bea] 204/158 [22] Filed: Feb. 22, 1974 OTHER PUBLICATIONS [21] App]. No.: 446,198

Related US. Application Data Continuation-impart of Ser. No. 256,175, May 23, 1972, abandoned, which is a continuation-in-part of Ser. No. 34,518, May 4, 1970, Pat. No. 3,728,382.

Schneider, Chem. Comm., 304, (1969).

Primary Examiner-Robert Gerstl Attorney, Agent, or Firm-Morris L. Nielsen 5 7 ABSTRACT Prostaglandin F -type compounds with a methyl or an ethyl substituent at C-15. These are useful for the same pharmacological purposes as the unsubstituted prostaglandins.

8 Claims, N0 Drawings IS-METHYL AND IS-lETHYL IPROSTAGLANDIN 13,, ANALOGS CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-impart of my copending application Ser. No. 256,175 filed May 23, 1972 now abandoned which was a continuation-impart of my then copending application Ser. No. 34,518 filed May 4, 1970, now issued as US. Pat. No. 3,728,382.

DESCRIPTION OF THE INVENTION This invention relates to novel compositions of matter, to novel methods for producing those, and to novel chemical intermediates useful in those processes. In particular, this invention relates to novel derivatives of prostanoic acid which has the following structure and atom numbering:

Various derivatives of prostanoic acid are known in the art. These are called prostaglandins. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein For example, prostaglandin E (PGE has the following structure:

Prostaglandins with a secondary alpha or beta hydroxy in place of the ring oxo of the prostaglandins E are also known. These are called prostaglandins F. For example, prostaglandin F20 (PGIFZQ) has the following StIUCtLII'CI Prostaglandin F2 (PGF has the following structure:

Prostaglandins F and F 3 corresponding to PGE,, PGE and dihydro-PGE are also known.

In formulas II to VII, broken line attachments to the cyclopentane ring indicate substituents in alpha config uration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring. The side-chain hy droxy at C- l 5 in formulas II to VII is in S configuration. See Nature, 212, 38 1966) for discussion of the stereo chemistry of the prostaglandins.

Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e., the dextrorotatory and levorotatory forms. As drawn, formulas II to VII each represent the particular optically active form of the prostaglandin which is obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, or human seminal plasma, or by carbonyl and/0r double bond reduction of a prostaglandin so obtained. See, for example, Bergstrom et al., cited above. The mirror image of each of formulas II to VII would represent the other enantiomer of that prostaglandin. The racemic form of a prostaglandin would contain equal numbers of both enantiomeric molecules, and one of formulas II to VII and the mirror image of that formula would both be needed to represent correctly the corresponding racemic prostaglandin. For convenience hereinafter, use of the terms PGE PGE PGE3, dihydro-PGE PGF PGFz PGF dihydrO-PGF PGF PGF PGF and dihydro-PGF will mean the optically active form of that prostaglandin with the same absolute configuration as PGE 1 obtained from mammalian tissues. When reference to the racemic form of one of those prostaglandins is intended, the word racemic' will preceed the prostaglandin name, thus, racemic PGE or racemic PGF Each of the novel prostanoic acid derivatives of this invention is encompassed by one of the following formulas or by the combination of that formula and its mirror image:

VIII

XII

XIII

In formulas VIII to XIII, R is hydrogen, alkyl of one to 8 carbon atoms, inclusive, or a pharmacologically acceptable cation, R is methyl or ethyl, and X is oxo, alpha hydroxy, or beta hydroxy, i.e.,

J. Chem. Education, 41, 1 I6 (1964), for discussion of S and R configurations.

A significant characteristic of all of the known prostaglandins is the secondary hydroxy group at C-l5, i.e., the atom grouping Prostaglandins obtained from animal tissues always contain that atom grouping. In striking contrast, each of the novel prostanoic acid derivatives of this invention has a tertiary hydroxy group at C-15, i.e., the atom grouping ..c R5 "OH or the corresponding R configuration grouping ,C- Rg 50H wherein R is methyl or ethyl. Thus, these novel prostanoic acid derivatives may conveniently be designated IS-methyl-prostaglandins or IS-ethyl-prostaglandins, e.g., 15-methyl-PGE2, l5-ethyI-PGF and 15- methyl-l 5 (R)-PGF2 As in the case of formulas II to VII, formulas VIII to XIII are each intended to represent optically active prostanoic acid derivatives having, except for the hydroxy at C-9 or C-IS in certain compounds, the same absolute configuration as PGE obtained from mammalian tissues. In addition, the novel prostanoic acid derivatives of this invention also include the corresponding racemic compounds. One of formulas VIIIXIII, inclusive, plus the mirror image of that formula are necessary in combination to describe a racemic compound. For convenience hereinafter, when the word racemic precedes the name of one of the novel prostanoic acid derivatives of this invention, the intent is to designate a racemic compound represented by the combination of the appropriate formula VIII to XIII and the mirror image of that formula. When the word racemic does not precede the compound name, the intent is to designate an optically active compound represented only by the appropriate formula VIII to XIII and with the same absolute configuration as IGE obtained from animal tissues.

PGE, PGE- PGE dihydro-PGE,, and the corresponding PGF and PGF compounds, and their esters and pharmacologically acceptable salts are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 1968), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGE and PGF compounds as measured, for example, in anesthetized (pentobarbital sodium) pentolinium-treated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for the PGFa compounds; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of the PGE compounds as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen; and in the case of the PGE compounds, stimulation of epidermal prolifera tion and keratinization as shown when applied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, and especially the PGE compounds, are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about ,ug. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

The PGE compounds are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 ,ug. to about 500 pg. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGE, PGFQ and PGFp compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent postoperative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations; the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGE, PGF and PGF compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of iso lated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggre gated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimu lators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs, thereof. Therefore PGE for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperioum. For the latter purpose, the PGE compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 too about 50 pg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

The PGE and PGF compounds are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 pg. per kg. of body weight per minute, or in single or multiple doses of about 25 to 500 pg. per kg. of body weight total per day.

The PGE, PGFO. and PGF 3 compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose 0.01 to 50 pg. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to hours after the membranes have ruptured and natural labor has not yet started.

The PGF PGF and PGE compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. For that purpose, PGE or PFG a for example, is administered systemically, e.g., intravenously, subcutaneously and intravaginally, at a dose level in the range 0.001 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the next expected time of menses of just prior to that time. Additionally, expulsion of an embryo or fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.

As mentioned above, the PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e. g., diabetes mellitus, vascular diseases, and hyperthyroidism.

The PGF 3 compounds are also useful in reducing the undesirable gastrointentinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of the PGF,; type prostaglandin and the anti-inflammatory prostaglandin synthetase inhibitor. See Partridge et al., US. Pat. No. 3,781,429, for a disclosure that the ulcerogenic effect induced by certain non-steroidal antiinflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins of the E and A series, including PGE PGE PGE 13,14- dihydro-PGE and the corresponding ll-deoxy-PGE and PGA compounds. PGF 5 compounds are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in Partride et al., as none-steroidal anti-inflammatory agents. But these are also known to be prostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, for example, indomethacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the known routes of systemic administration.

The prostaglandin of the PGF B -type is administered along with the antiinflammatory prostaglandin synthetase inhibitor either by the same route of admin istration or by a different route. For example, if the anti-inflammatory substance is being administered orally, the PGF -type prostaglandin is also administered orally or, alternatively, is administered rectally in the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example as described in US. Pat. No. 3,545,439. Alternatively, if the anti-inflammatory substance is being administered rectally, the PGF g type prostaglandin is also administered rectally or alternatively, orally or, in the case of women, vaginally. It is especially convenient when the administration route is to be the same for both anti-inflammatory substance and PGF 3 -type prostaglandin, to combine both into a single dosage form.

The dosage regimen for the PGF 5 -type prostaglan din in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular individual mammal to the particular synthetase inhibitor with regard to gastrointestinal effects, and the particular PGF 3 type prostaglandin to be administered. For example, not every human in need of an anti-inflammatory substance experiences the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree. But it. is within the skill of the attending physician or veterinarian to determine that administration of the antiinflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject and to prescribe an effective amount of the PGF 3 -type prostaglandin to reduce and then substantially to eliminate those undesirable effects.

Among the PGF 3 compounds, PGE B -type compounds are preferred.

The novel IS-methyl and l5-ethyl prostaglandin analogs encompassed by formulas Vlll to XIII, the corresponding R and S 15-methyl and IS-ethyl PGE PGF a and PGF, [3 compounds, and also the corresponding racemic analogs each cause the same biological responses described above for the corresponding known prostaglandins. Each of these 15-methyl and 15- ethyl compounds is accordingly usefiil for the abovedescribed pharmacological purposes, and is used for those purposes as described above. However, each of these l5-methyl and IS-ethyl prostaglandin analogs is surprisingly and unexpectedly more useful than the corresponding known prostaglandin for at least one of the pharmacological purposes described above because for that purpose the analog is more potent and has a substantially longer duration of activity. For that reason, fewer and smaller doses of these prostaglandin analogs are needed to attain the desired pharmacological results.

The novel l5-methyl-PGF compound and its racemic form are useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandinsynthetase inhibitors discussed above. The compounds having the C-l5 hydroxy in beta (R) configuration are also useful for this purpose when administered orally.

For the above purpose, the total daily dose of PGF B is in the range of about 0.025 mg. to about 25 mg. per kg. of body weight; for lS-methyl-PGF the range is about 2.5 ug. to about pg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The novel PGE-type, PGF -type, and PGF 3 -type analogs encompassed by formulas VIII to Xlll the corresponding R and S PGE,, PGE and PGF analogs, and also the corresponding racemic analogs are used as described above in free acid form, in alkyl ester form, or in pharmacologically acceptable salt form. When the ester form is used, any alkyl ester can be used wherein the alkyl moiety contains one to eight carbon atoms, inclusive, i.e, methyl. ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. However, it is preferred that the ester be alkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system.

Pharmacologically acceptable salts of these prostaglandin analogs useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylarnine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, clicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, B-phenylethylamine, ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e. g. l-methylpiperidine, 4- ethylmorpholine, l-isopropylpyrrolidine, 2- methylpyrrolidine, l ,4-dimethylpiperazine, 2'

methylpiperdine, and the like, as well as amines containing watersolubilizi'ng or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, Z-amino-l-butanol, 2-amino-2- ethyl-1,3-propanediol, 2-amino-2-methyll -propanol, tris( hydroxymethyl )aminomethane, N- phenylethanolamine, N-(p-tertamylphenyl)diethanolamine, galactamine, N-methylglucamine, N- methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the prostaglandin analogs are administered in various ways for various purposes; e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubility to use the free acid form or the pharmacologically acceptable salt form. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administra tion. For rectal or vaginal administration, suppositories, tampons, ring devices, and preparations adapted to generate sprays or foams or to be used for lavage, all prepared as known in the art, are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the sub stance is used.

The novel PGE-type acids and alkyl esters of formulas Vlll to XIII wherein X is =0, aind also the corresponding R and S PGE -type acids and alkyl esters are prepared by oxidation of the corresponding PGF type or PGF -type acids and alkyl esters. For this purpose, an oxidizing agent isused which selectively oxidizes secondary hydroxy groups to carbonyl groups in the presence of carbon-carbon double bonds. These transformations are shown in Chart A, wherein the formulas as drawn represent optically active compounds. When the same process steps are applied to the corresponding racemic starting materials consisting of the optically active compounds as depicted and the mirror images thereof, those process steps yield the cone sponding racemic intermediates or racemic prostaglandin analogs. Likewise, the corresponding IS-epimeric starting materials of either the optically active compounds or their racemates yield the corresponding 15- epimeric products. Also in Chart A, R is methyl or ethyl, R is hydrogen or alkyl of one to eight carbon atoms, inclusive, X and Y are both -CH CH or X is trans-Cl-I=CH and Y is -CH Cl-l or cisCI-l==CI-I, and indicates attachment of hydroxy to the ring in alpha or beta configuration.

For the transformation of Chart A, the beta isomers of reactants XIV and XVI are preferred starting materials although the corresponding alpha isomers are also useful for this purpose.

Oxidation reagents useful for the transformations set forth in Chart A are known to the art. An especially useful reagent for this purpose is the Jones reagent, i.e., acidified chromic acid. See J. Chem. Soc. 39 (I946). Acetone is a suitable diluent for this purpose, and a slight excess beyond the amount necessary to oxidize one of the secondary hydroxy groups of the formula XIV or XVl reactant is used. Reaction temperatures at least as low as about 0 C. should be used. Preferred re action temperatures are in the range l0 to 50 C. The oxidation proceeds rapidly and is usually complete in about 5 to about 20 minutes. The excess oxidant is destroyed, for example, by addition of a lower alkanol, advantageously, isopropyl alcohol, and the formula XV or XVII PGE-type product is isolated by conventional methods.

CHART A XVI (Oxidation) Examples of other oxidation reagents useful for the Chart A transformations are silver carbonate on Celite (Chem. Commun. 1 I02 1969)), mixtures of chromium trioxide and pyridine (Tetrahedron Letters 3363 (1968), J. Am. Chem. Soc. 75, 422 (1953), and Tetrahedron, I8, 1351 1962)), mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide (J. Am. Chem. Soc. 89, 5505 (1967)), and mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87,5661 (1965)).

The novel PGF (1 -type and PGF -type acids and esters of formulas VIII to XIII wherein X is and also the corresponding PGF a -type and PGF, B type acids and alkyl esters are prepared by the sequence of transformations shown in Charts B and C, wherein the formulas as drawn represent optically active compounds. The corresponding racemic starting materials yield the corresponding racemic intermediates or racemic prostaglandin analogs, applying the process steps of Charts B and C. Also in Charts B and C, R is methyl or ethyl, R is hydrogen or alkyl of one to 8 carbon atoms, inclusive, X and Y are both -CH CH or X is trans-CH=CH- and Y is -CH CH or cisCH=Cl-I, and indicates attachment of hydroxy to the ring in alpha or beta configuration. Also in Charts B and C, A is alkyl or one to four carbon atoms, inclusive, aralkyl of seven to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one or 2 fluoro, ehloro, or alkyl of one to four carbon atoms, inclusive, and R is alkyl of one to eight carbon atoms, inclusive, or -Si(A) wherein A is as defined above.

(A) -Si-0 CHART c (hydrolysis) WCOOR In Charts B and C, the final PGF :1 and PGF 3 products are those encompassed by formulas XXI XXII and XXVI XXVII, respectively.

The initial optically active reactants of formulas XVIII and XXIII in Charts B and C, i.e., PGF PGF PGF PGF B PGF PGF dihy' dro-PGF, a and dihydro-PGF B and their alkyl esters are known in the art or are prepared by methods known in the art. See, for example, Bergstrom et al., cited above, US. Pat. No. 3,069,322, and British Specification No. 1,040,544. The initial racemic reactants of formula XVIII in Chart B, i.e., racemic PGF a racemic PGF racemic PGF, racemic PGF racemic PGE, and racemic PGE, )3 and their alkyl esters are known in the art or are prepared by methods known in the art. See, for example, .Just et al., J. Am. Chem. Soc. 91, 5364 (1969), Corey et al., J. Am. Chem. Soc. 90, 3245 (1968), Schneider et al., Chemical Communications (Great Britain), 304, 1969), and Axen, Chemical Communications, 602 (1970).

Racemic dihydro-PGF and racemic dihydro- PGF p and their esters are prepared by catalytic hydrogenation of the corresponding racemic PGF a or PCP and PGF or PUP- compounds, respectively, for example, in the presence of 5% palladiumon-charcoal catalyst in ethyl acetate solution at 25 C. and one atmosphere pressure of hydrogen.

The known acids and esters of formulas XVIII and XXIII are transformed to the corresponding intermediate 15-0xo acids and esters of formulas XIX and XXIV, respectively, by oxidation with reagents such as 2,3- dichloro-S ,6-dicyano- 1 ,4-benzoquino ne, activated manganese dioxide, or nickel peroxide (see Fieser et al., Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., pp. 215, 637, and 731). Alternatively, and especially for the formula XVIII reactants wherein X and Y are CH CH these oxidations are carried out by oxygenation in the presence of the l5-hydroxyprostaglandin dehydrogenase of swine lung (see Arkiv for Keml' 25, 293 (1966)). These reagents are used according to procedures known in the art. See, for example, J. Biol. Chem. 239, 4097 1964).

Referring again to Charts B and C, the intermediate compounds of formulas XIX and XXIV are transformed to silyl derivatives of formulas XX and XXV, respectively, by procedures known in the art. See, for example, Pierce, Silylation of Organic Compounds, Pierce Chemical Co., Rockford, Ill. (1968). Both hydroxy groups of the formula XIX and XXIV reactants are thereby transformed to -OSi(A) moieties wherein A is as defined above, and sufficient of the silylating agent is used for that purpose according to known procedures. When R in the formula XIX or XXIV intermediate is hydrogen, the -COOI-I moiety thereby defined is simultaneously transformed to -COOSi(A) additional silylating agent being used for this purpose. This latter transformation is aided by excess silylating agent and prolonged treatment. When R in formulas XIX and XXIV is alkyl, then R in formulas XX and XXV will also be alkyl. The necessary silylating agents for these transformations are known in the an or are prepared by methods known in the art. See, for example, Post, Silicones and Other Organic Silicon Compounds," Reinhold Publishing Corp., New York; N.Y. (1949).

Referring again to Charts B and C, the intermediate silyl compounds of formulas XX and XXV are transformed to the final compounds of formulas XXI XXII and XXVI XXVII, respectively, by first reacting the silyl compound with a Grignard reagent of the formula R MgX wherein R is methyl or ethyl, and X is chloro, bromo, or iodo. For this purpose, it is preferred that X be bromo. This reaction is carried out by the usual pro cedure for Grignard reactions, using diethyl ether as a reaction solvent and saturated aqueous ammonium chloride solution to hydrolyze the Grignard complex. The resulting disilyl or trisilyl tertiary alcohol is then hydrolyzed with water to remove the silyl groups. For this purpose, it is advantageous to use a mixture of water and sufficient of a water-miscible solvent, e.g., ethanol to give a homogenous reaction mixture. The hydrolysis is usually complete in 2 to 6 hours at 25 C., and is preferably carried out in an atmosphere of an inert gas, e.g., nitrogen or argon.

The mixture of 15-8 and 15-R isomers obtained by this Grignard reaction and hydrolysis is separated by procedures known in the art for separating mixtures of prostanoic acid derivatives, for example, by chromatography on neutral silica gel. In some instances, the lower alkyl esters, especially the methyl esters of a pair of 15-8 and l5-R isomers is more readily separated by silica gel chromatography than are the corresponding acids. In those cases, it is advantageous to esterify the mixture of acids as described below, separate the two esters, and then, if desired, saponify the esters by procedures known in the art for saponification of prostaglandins F.

Although formula XXI and XXII compounds wherein X and Y are both CH CH are produced according to the processes of Chart B, it is preferred to produce those novel dihydro-PGF analogs by hydrogenation of one of the corresponding unsaturated compounds, i.e., a compound of formula XXI or XXII wherein X is trans-CI-I=CI-I and Y is CI-I CH or cisCH%3I-I, or a compound of formula XXVI or XXVII. This hydrogenation is advantageously carried out catalytically, for example, in the presence of a 5% palladium-on-charcoal catalyst in ethyl acetate solution at 25 C. and one atmosphere pressure of hydrogen.

As discussed above, the processes of Charts A, B, and C lead either to acids (R is hydrogen) or to alkyl esters (R is alkyl of one to eight carbon atoms, inclusive). When a formula XXI, XXII, XXVI, XXVII PGF-type acid or a formula XV or XVII PGE-type acid (Chart A) has been prepared and an alkyl ester is desired, esterification is advantageously accomplished by interaction of the acid with the appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane, and l-diazo-Z-ethylhexane, for example, gives the ethyl, butyl, and Z-ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventipnal methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reactions, John Wiley & Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxyl moiety of the PGF-type or PGE-type compounds comprises transformation of the free acid to the corresponding silver salt, followed by interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, and the like. The silver salts are prepared by conventional methods, for example, by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometric amount of silver nitrate.

The novel formula VIII to XIII acids (R is hydrogen) are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium, salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt of the prostanoic acid derivative. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acid is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixing the acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.

The invention can be more fully understood by the following examples.

Infrared absorption spectra are recorded on a Perkin- Elmer model 421 infrared spectrophotometer. Undiluted (neat) samples of the liquids and oils are used. Mineral oil (Nujol) mulls of the solids are used.

NMR spectra are recorded on a Varian A-60 spectrophotometer with tetramethylsilane as an internal stan dard (downfield) and using solvents as indicated below.

Mass spectra are recorded'on an Atlas CH-4 mass spectrometer with a TO-4 source (ionization voltage ev).

The term 15'oxoin front of a compound name, e,g., l-oxo-PGF refers to a prostaglandin analog wherein the moiety at the l5-position has been transformed to EXAMPLE 1 -Oxo-PGF 2,3-Dichloro-5 ,6-dicyano-1,4-benzoquinone (463 mg.) is added to a solution of PGF (600 mg.) in 30 ml. of dioxane. The mixture is stirred 24 hours at 50 C. under nitrogen, and then is cooled to C. and filtered. The filtered solids are washed with dichloromethane. Evaporation of the combined filtrate and washings at reduced pressure gives 650 mg. of a residue which is chromatographed on 150 g. of silica gel (Silicar C C-4; Mallincrodt), eluting with 50% ethyl acetate in Skellysolve B (a mixture of isomeric hexanes). Evaporation of the eluates gives 545 mg. of l5-oxoPGF infrared absorption at 3400, 2660, 1700, 1660, 1620, 1460, 1410, 1375, 1285, 1250, 1185, 1120, 1070, and 980 cm.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone 1.0 g.) is added to a solution of PGF Q (1.3 g.) in 80 ml. of dioxane. The mixture is stirred 24 hours at 50 C. under nitrogen, and is then cooled to 20 C. and filtered. The filtered solids are washed with dichloromethane. Evaporation of the combined filtrate and washings at reduced pressure gives 1.6 g. of a residue which is chromatographed on 400 g. of silica gel (Silicar CC-4; Mallincrodt), eluting with 75% ethyl acetate in Skellysolve B. Evaporation of the eluates gives 1.15 g. of l5-oxo- PGF B infrared absorption at 3380, 2660, 1720, 1705, 1665, 1620, 1460, 1405, 1370, 1325, 1285, 1235, 1190, 1080, 1040, and 980 cm.

EXAMPLE 3 l5-Oxo-PGF Following the procedure of Example 1, POE is oxidized to l5-oxo-PGF infrared absorption at 3400, 2660, 1705, 1660, 1625, 1405, 1375, 1320, 1290,1245-1225, l2l5l 175, 1115, 1075, 1050, and 980 cm.

Following the procedure of Example 1, PGFm is oxidized to 15oxo-PGF infrared absorption at 3380, 3010, 2650, 1705, 1655, 1625, 1320,1295, 1245l225, 1190, 1085, 104-0, and 980 cm.

EXAMPLE 5 Following the procedure of Example 1, PGF oxidized to l5-oxo-PGF EXAMPLE 6 IS-OXO-PGFMQ EXAMPLE 7 Dihydrol S-oXo-PGF Following the procedure of Arkiv for Kemi, 25, 293 (1966), dihydro-PGF is oxidized to dihydro-l5- oxo-PGF with the l5-hydroxyprostaglandin dehydrogenase enzyme of swine lung.

Following the procedure of Example 7, dihydro- PGF is oxidized to dihydrol-l5-oxo-1PGF 5 Also following the procedure of Example 7, the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of dihydro-PGF and dihydro-PGF fl are each oxidized to the corresponding l5-oxo compounds.

Also following the procedure of Example 7, the racemic forms of dihydro-PGF dihydro-PfiF fl and the methyl, ethyl, tert-butyl, and 2ethylhexyl esters of each of those are each oxidized to the corresponding racemic l5-oxo compound.

EXAMPLE 8 Tris-(trimethylsilyl) Derivatives of l5Oxo-PGF A mixture of hexamethyldisilazane (l 1 ml.) and trimethylchlorosilane (2.2 ml.) is added to a solution of l5-oxo-PGF (545 mg.) in 55 ml. of tetrahydrofuran. This mixture is stirred 16 hours at 25 C. under nitrogen, and is then filtered. The filtrate is evaporated under reduced pressure. Xylene (50 ml.) is added to the residue and the mixture is evaporated at 60 C. under reduced pressure. This addition of xylene and evaporation is repeated twice. The resulting residue is the tris-(trimethylsilyl) derivative of 15-oxo-PGF infrared absorption at 1365, 1250, and 1180 cm.

EXAMPLE 9 Tris-(trimethylsilyl) Derivatives of lS-OXO-PGF fi.

Following the procedure of Example 8, l5-oxo- PGF g is transformed to the tris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680, 1635, 1375, 1250, 1180, 1065, 980, 840, and 750 cm.

EXAMPLE l Tris-(trimethylsilyl) Derivative of l-Oxo-PGF Following the procedure of Example 8, l5oxo PGF is transformed to the tris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680, 1635, 1250, and 845 cm.

EXAMPLE ll Tris-(trimethylsilyl) Derivative of -Oxo-PGF fi Following the procedure of Example 8, l5-oxo- PGF g is transformed to the tris-(trimethylsilyl) derivative; infrared absorption at 1725, 1680, 1635, 1250, and 845 cm.

EXAMPLE 12 Tris(trimethylsilyl) Derivative of l5-Oxo-PGF Following the procedure of Example 8, 15-oxois transformed to the tris-(trimethylsilyl) derivative.

EXAMPLE 13 Tris-(trimethylsilyl) Derivative of l5-Oxo-PGF fl,

Following the procedure of Example 8, l5-oxo- PGF Q is transformed to the tris-trimethylsilyl) derivative.

EXAMPLE 14 Tris-( trimethylsilyl) Derivative of Dihydro15-oxo-PGF Following the procedure of Example 8, dihydro-lS- oxo-PGF is transformed to the tris-(trimethylsilyl) derivative.

EXAMPLE 14A Tris-(trimethylsilyl) Derivative of Dihydrol5oxo-PGF 5,

Following the procedure of Example 8, dihydro-l5 oxo-PGF fl is transformed to the tris-(trimethylsilyl) derivative.

Following the procedure of Example 8, the methyl, ethyl, tert-butyl, and 2ethyl-hexyl esters of 15-oxo- PGF l5-oxoPGF l5-oxo-PGF l5oxo- PGF B l5-oxo-PGF l5-OXOPGF B dihydrol5-0xo-PGF, and d1l'lydIOl5-OXOPGF fl are each transformed to the corresponding bis- (trimethylsilyl) derivative.

Also following the procedure of Example 8, the racemic forms of l5-oxo-PGF l5-oxo-PGF fi l5- oxo-PGF l5-oxo-PGF B l5-oxo-PGF l5- oxo-PGF dihydro-lS-oxo-PGF dihydro-lS- oxo-PGF g and the methyl, ethyl, tert-butyl, and 2- ethylhexyl esters of each of those are each transformed to trimethylsilyl derivatives, the acids to tris derivatives and the esters to bis derivative.

Also following the procedure of Example 8 but using appropriate reactants in place of the hexamethyldisilazane and trimethylchlorosilane, there are prepared the tris-(triphenylsilyl) and tris-(tribenzylsilyl) derivatives of l5-oxo-PGF l5-oxo-PGF B l5-oxo- PGF l5-oxo-PGF fl l5-oxo-PGF l5-oxo- PGF dihydro-lS-oxo-PGF ,and dihydro-lS- oXo-PGF B and of the racemic forms of each of those acids, and also the bis-(triphenylsilyl) and bis- (tribenzylsilyl) derivatives of the corresponding methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those optically active and racemic acids.

EXAMPLE l5 lS-Methyl-PGF and 15-Methyl-l5(R)-PGF,

A 3 molar diethyl ether solution of methylmagnesium bromide (0.55 ml.) is added dropwise to a stirred solution of the tris-(trimethylsilyl) derivative of l5-oxo- PGF (850 mg.) in 25 ml. of diethyl ether at 25 C. The mixture is stirred 30 minutes at 25 C., after which an additional 0.2 ml. of the methylmagnesium bromide solution is added and stirring is continued an additional 30 minutes. The resulting reaction mixture is poured into ml. of saturated aqueous ammonium chloride solution at 0 C. After stirring several minutes, the mixture is extracted repeatedly with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of the diethyl ether gives a yellow oil (910 mg.) which is dissolved in 45 ml. of ethanol. That solution is diluted with 30 ml. of water, and the mixture is stirred 4 hours at 25 C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is saturated with sodium chloride and then extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to give 640 mg. of a mixture of IS-methyl- PGF and l5-methyl-l5(R)-PGF infrared absorption at 3280, 2600, and 1710 cm.

The mixture of IS-methyl-PGF and lS-methyll5(R)-PGF is dissolved in 50 ml. of diethyl ether and cooled to 0 C. Excess diazomethane dissolved in diethyl ether is then added, and the mixture is maintained 5 minutes at 0 C. and then 5 minutes at 25 C. The solution is evaporated in a stream of nitrogen, and the residue is chromatographed on 550 g. of neutral silica, eluting with 75% ethyl acetate in Skellysolve B. Evaporation of eluate fractions gives, successively, 127 mg. of l5-methyl-l5(R)-PGF methyl ester, mg. of a mixture of 15-methyl-15(R)-PGF methyl ester and IS-methyl-PGF methyl ester, and 228 mg. of l5-methyl-PGF 1a methyl ester. The latter crystallizes on standing; m.p. 7275 C.; mass spectral molecular ion peaks at 366, 348, 317, 313, and 294.

Aqueous potassium hydroxide solution (45%; 0.9 ml.) is added to a solution of IS-methyl-PGF methyl ester (228 mg.) in a mixture of 6.8 ml. of methanol and 2.2 ml. of water under nitrogen. The resulting solution is stirred 2 hours at 25 C., and is then poured into several volumes of water. The aqueous mixture is extracted with ethyl acetate, acidified with 3 N hydrochloric acid, saturated with sodium chloride, and then extracted repeatedly with ethyl acetate. The latter ethyl acetate extracts are combined, washed successively with water and saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. The crystalline residue is recrystallized from a mixture of ethyl acetate and Skellysolve B to give lS-methyl-PGF ;m.p 81-83 C.; infrared absorption at 3410, 3300, 2650, 1705, 1305, 1290, 1275, 1255, 1220, 1195, 1125, 1075, 980, and 915 cm; NMR peaks (dimethylformamide) at 5.5 and 4.4-3.6 (multiplet) 8; mass spectral molecular ion peaks at 643, 587, and 568.

Following the above procedure. l-methyl-15(R) PGF methyl ester is saponified to l5-methyl-15(R)- PGF infrared absorption at 3380, 2650, 1710, 1460, 1410, 1375, 1275l200, 1125, 1075, 1040, and 975 cm"; NMR peaks (dimethylformamide) at 5.50 and 4.40-3.60 (multiplet) 6; mass spectral molecular ion peaks at 352, 334, 316, and 263.

EXAMPLE 16 IS-MethyI-PGF and l5-Methyl-l5(R)-PGF,

A 3 molar diethyl ether solution of methylmagnesium bromide (0.67 ml.) is added dropwise to a stirred solution of the tris(trimethylsilyl) derivative of -oxo- PGF (910 mg.) in 25 ml. of diethyl ether at 25 C. The mixture is stirred 30 minutes at 25 C., after which an additional 0.3 ml. of the methylmagnesium bromide solution is added and stirring is continued an additional 15 minutes. The resulting reaction mixture is poured into a mixture of ice and 75 ml. of saturated aqueous ammonium chloride solution. After stirring several minutes, the mixture is extracted repeatedly with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of: the diethyl ether at reduced pressure gives a colorless, viscous oil which is dissolved in 30 ml. of ethanol. That solution is diluted with ml. of water, and the mixture is stirred 3 hours at C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is diluted with an equal volume of saturated aqueous sodium chloride solution and then extracted repeatedly with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated at reduced pressure to give 700 mg. of a crystalline mixture of IS-methyI-PGF fi and l5-methyl-l5(R)-PGF Recrystallization of this mixture three times from ethyl acetate containing a trace of methanol gives l5-methyl-PGF, B m.p. 164l64.5 C.; infrared absorption at 3250, 3160, 2700, 1710, 1330, 1315, 1305, 1085, 1035, and 970 cm; NMR peaks (dimethylformamide) at 5.53 (doublet), 5.103.6 (multiplet), and 1.20 (singlet) 5; mass spectral molecular ion peaks at 370, 352, and 334.

l5-Methyl-15(R)-PGF p is obtained from the above described recystallization mother liquors.

EXAMPLE 17 IS-MethyI-PGF and l5-Methyl-l5(R)-PGF Following the procedure of Example 15, the tris- (trimethylsilyl) derivative of l5-oxo-PGF (500 mg.) is transformed first to a mixture of l5-methyl PGF and l5-methyl-15(R)PGF and then to the corresponding mixture of methyl ethers. This methyl ester mixture (520 mg.) is chromatographed on 500 g. of neutral silica gel (Merck), eluting successively with 21. of 20%, 6 l. of40%, and 8 l. of 50% ethyl acetate in Skellysolve B. The corresponding eluates emerging from the column are discarded. Elution is continued successively with gradients of 4 l. of 50% and 4 l. of 60% ethyl acetate in Skellysolve B, and 5 l. of 60% and 5 l. of ethyl acetate in Skellysolve B, and then with l. 1. of 75% ethyl acetate in Skellysolve B, collecting the corresponding eluates in 500-ml. fractions. Elution is further continued successively with 5 l. of 75% ethyl acetate in Skellysolve B and with 6 l. of

% ethyl acetate, collecting the corresponding eluates in 200-ml. fractions. Eluate fractions 29-35 are combined and evaporated to give 109 mg. of 15- methyl-l5(R)-PGF methyl ester. Eluate fractions 39-67 are combined and evaporated to give mg. of lS-methyl-PGF a methyl. ester.

Following the procedure of Example 15, 15-methyl- PGF methyl ester is saponified to give l5-methyl- PGF infrared absorption at 3260, 2600, 1710, 1365, 1235, 1040, and 970 cm; NMR peaks (deuterochloroform) at 5.82, 5.655.15 (multiplet), and 4,2-3.8 6; mass spectral molecular ion peaks at 350, 332, and 314.

Also following the procedure of Example l5, l5- methyl-l5(R)-PGF methyl ester is saponified to l5 methyl-l5(R)-PGF infrared absorption at 3250, 2600, 1710, 1235, 1040, and 970 cm; NMR peaks (deuterochloroform) at 6.15 (singlet), 4.20-3.8 (multi plet), and 0.90 (triplet).

EXAMPLE l8 15Methyl-PGF and l5-Methyl-l5(R)-PGF B,

Following the procedure of Example 15, the tris- (trimethylsilyl) derivative of l5-oxo-PGF fi (5.1 g.) is reacted with a total of 8 ml. of 3 molar methylmagnesium bromide in diethyl ether, and the product is by drolyzed to give a mixture of IS-methyl-PGF p and l5-methyl-l5(R)-PGF 3 (4.37 g.) in the form ofa dark oil. Crystallization of this oil from a mixture of methanol and ethyl acetate, and recrystallization of the resulting crystals from a mixture of the same solvents gives IS-methyl-PGF Q m.p. l34134.5 C; infrared absorption at 3250, 3180, 2720, 1710, 1345, 1305, 1235, 1085, 1050, 970, and 920 cm; NMR peaks (dimethylsulfoxide) at 5.46 (doublet), 5.0-4.0, and 3.8 (multiplet) 6; mass spectral molecular ion peaks at 368, 350, 332, 314, 297, 278, and 205.

l5-Methyl-l5(R)-PGF B is obtained from the mother liquors of the above crystallization and recrystallization' of l5-methyl-PGF fi EXAMPLE l9 IS-Methyl-PGF and l5-Methyl-l5(R)-PGF Following the procedure of Example 15, the tris- (trimethylsilyl) derivative of 15-oxo-PGF is reacted with methylmagnesium bromide, and the product is hydrolyzed .to give a mixture of l5methyl-PGF and 15-methyl-l5(R)-PGF This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified to give 15-methyl-PGF and 15-methyl-l5(R)-PGF as described in Example 15. Alternatively, the mixture of acids is separated as described in Example 16.

EXAMPLE 20 l5-Methyl-PGF and IS-Methyl- 1 5 R)-PGF B Following the procedure of Example 15, the tris- (trimethylsilyl) derivative of l5-oxo-PGF is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of IS-methyI-PGF B and 15-methyl-15(R)-PGF p This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 15. Alternatively, the mixture of aicds is separated as described in Example 16.

EXAMPLE 2 l Dihydro- 1 S-Methyl-PGF and Dihydro-15-Methyl-15(R)-PGF Following the procedure of Example 15, the tris- (trimethylsilyl) derivative of dihydro- 1 -oxo-PGF a is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of dihydro-IS- methyl-PGF a and dihydro-l5-methyl-15(R)- PGF This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 15. Alternatively, the mixture of acids is separated as described in Example 16.

EXAMPLE 22 Dihydrol5-Methyl-PGF B and Dihydro-l5-Methyl-15(R)-PGF B Following the procedure of Example 15, the tris- (trimethylsilyl) derivative of dihydro-l5-oxo-PGF is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of dihydro-- methyl-PGF B and dihydro-l5-methyl-l5(R)- PGF p This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 15. Alternatively, the mixture of acids is separated as described in Example 16.

Following the procedure of Example 15, the methyl, ethyl, tert-butyl, and 2-ethyl-hexyl esters of the bis- (trimethylsilyl) derivatives of IS-OXO-PGFm, l5-oxo- PGF p l5-oxo-PGF l5-oxo-PGF B l5-oxo- PGF l5-oxo-PGF B dihydro-l5-oxo-PGF 1a and dihydro-l5-oxo-PGF p are each transformed to the corresponding l5-methyl and 15-methyl-15(R) esters.

Also following the procedure of Example 15, the racemic forms of the trimethylsilyl derivatives of 15-oxo- PGF l5oxo-PGF,B l5-oxo-PGF l5-oxo- PGF B 15-oxo-PGF 15oxo-PGF B dihydrol5-oxoPGF dihydro-lS-oxo-PGF and the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those, tris derivatives of the acids and bis derivatives of the esters, are each transformed to the corresponding l5-methyl and l5-methyll 5(R) acid or ester.

Also following the procedure of Example 15, the tris- (triphenylsilyl) and tris-(tribenzylsilyl) derivatives of l5-oxo-PGF l5-oxo-PGF,p l5-oxo-PGF l5-oxo-PGF l5-oxo-PGF l5-oxo-PGF;, dihydro-lS-oxo-PGF and dihydro-lS-oxo- PGR and of the racemic forms of each of those optically active acids, ahd also the bis-(triphenylsilyl) and bis-(tribenzylsilyl) derivatives of the corresponding methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those optically active and racemic acids are each transformed to the corresponding IS-methyl and l5-methyl-l5(R) acid or ester.

Also following the procedure of Example 15 but using ethylmagncsium bromide in place of the methylmagnesium bromide, the tris-(trimethylsilyl), tris- (triphenylsilyl), and the tris-(tribenzylsilyl) derivatives of l5-oxo-PGF l5-oxo-PGF B l5-oxo-PGF 15-oxo-PGF p l5-oxo-PGF ,15-oxo-PGF B dihydro-lS-oxo-PGF dihydro-15-oxo-PGF p and the racemic forms of each of those optically active acids, and also the bis-(trimethylsilyl), bis- (triphenylsilyl), and bis-(tribenzylsilyl) derivatives of the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those optically active and racemic acids are each transformed to the corresponding l5-ethyl and l5-ethyl-15(R) acid or ester.

EXAMPLE 23 1 5-Methy1-PGE A solution of l5-methyl-PGF p mg.) in 40 ml. of acetone is cooled to -10 C. Jones reagent (0.1 ml. of a solution of 21 g. of chromic anhydride, 60 ml. of

water, and 17 ml. of concentrated sulfuric acid), precooled to 0 C., is added with vigorous stirring. After 5 minutes at 10 C., thin layer chromatography on silica gel (acetic acidzmethanol:chloroform; 5:5:90) of a small portion of the reaction mixutre indicates about 50% reaction completion. An additional 0.06 ml. of Jones reagent is added to the still cold reaction mixture with stirring, and the mixture is stirred an additional 5 minutes at 10 C. Isopropyl alcohol (1 ml.) is added to the cold reaction mixture. After 5 minutes, the mixture is filtered through a layer of diatomaceous silica (Celite). The filtrate is evaporated at reduced pressure, and the residue is mixed with 5 ml. of saturated aqeuous sodium chloride solution. The mixture is extracted repeatedly with ethyl acetate, and the combined extracts are washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated at reduced pressure. The residue is chromatographed on 20 g. of neutral silica gel, eluting with 50% ethyl acetate in Skellysolve B. Evaporation of the eluates gives 29 mg. of lS-methyl-PGE mass spectral molecular ion peaks at 350, 332, 317, and 261.

EXAMPLE 24 l5-Methyl-PGE A solution of l5-methyl-PGF B (300 mg.) in ml. of acetone is cooled to 35 C. Jones reagent (0.2 ml.) is added with vigorous stirring, and stirring is continued for 15 minutes. At that point, thin layer chromatography on silica gel (acetic acid:methanol:- chloroform; 5:5:90) of a small portion of the reaction mixture indicates about 75% reaction completion. An additional 0.1 ml. of Jones reagent is added to the reaction mixture and stirring is continued at 35 C. for a total reaction time of 45 minutes. Isopropyl alcohol (1 m1.) is added to the cold reaction mixture which is then allowed to warm to 0 C. and is filtered through Celite. The filtrate is evaporated at reduced presusre, and the residue is dissolved in dichloromethane. That solution is washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated at reduced pressure. Each 50 mg. of residue is chromatographed on a thin layer plate (20 X 20 cm; with a 1000 ,u. layer of neutral silica gel), developing twice with the A-lX solvent system. The silica gel areas containing the desired product as shown by smallscale thin layer chromatography are removed from each plate, combined, placed on top of a neutral silica gel column, and eluted through the column with 10% methanol in ethyl acetate. Evaporation of the eluate EXAMPLE 25 l -Methyl-PGE Following the procedure of Example 24, lS-methyl- PGF B is oxidized to l5-methyl-PGE EXAMPLE 26 Dihydrol S-Methyl-PGE Following the procedure of Example 24, dihydro-l5- methyl-PGF,5 is oxidized to dihydro-lS-methyl- PGE EXAMPLE 27 IS-Methyll 5(R)-PGE Following the procedure of Example 24, IS-methyll5(R)-PGF p is oxidized to l5-methyl-l5(R)-PGE EXAMPLE 28 IS-Methyll 5(R)-PGE Following the procedure of Example 24, l5-methyll5(R)-PGF p is oxidized to l5-methyl-l5(R)-PGE EXAMPLE 29 l5-Methyll5(R)-PGE Following the procedure of Example 24, l5-methyll5(R)-PGF,, is oxidized to -methyl-15(R)-PGE EXAMPLE 3O Dihydro- 15(R )-PGE Following the procedure of Example 24, dihydro-l5- methyl-l5(R)-PGF B is oxidized to dihydro-lS- methyl-l5(R)-PGE,.

Following the procedure of Example 24, lS-methyl- PGF are each oxidized to the corresponding PGE compound.

Also following the procedure of Example 24, the methyl, ethyl, tert-butyl, and 2-ethyl-hexyl esters of l5- methyl-POP, l5-methyl-PGF B 15-methyll5(R)-PGF, l5-methyl-l5(R)-PGF B l5-methyldihydrol S-methyl-l 5(R)-PGF, and dihydro-lS- methyl-l5(R)-PGF,p are each oxidized to the corresponding 15-methyl-PGE or l5methyl-15(R)-PGE ester.

Also following the procedure of Example 24, the racemic forms of IS-methyl-PGF 1a lS-methyl- PGF B ,15-methyl-15(R)-PGF, 15-methyl-l5(R)- PGF IS-methyl-PGF- l5-methyl-PGF- p 15- methyl-l5(R)-PGF 15-me=thyl-l5(R)-PGF p l5- methyl-PGF 15-methyl-PGF B IS-methyll5(R)-PGE 15-methyl-15(R)-PGF dihydro-lS, 15methyl-15(R)-PGF dihydrol 5 -methyl-PGF dihydro- 1 S-methyl-PGF dihydr015-methyl-15(R)- PGFla, and dihydro-l5-me'thyl-15(R)-PGF and the methyl, ethyl, tert-butyl and 2-ethylhexyl esters of each of those racemic acids are each oxidized to the corresponding racemic IS-methyl-PGE or 15- methyl-15(R)-PGE acid or ester.

Also following the procedure of Example 24, 15- ethyl-PGF IS-ethyI-PGF p l5-ethyl-l5(R)- PGF l5-ethyl-l5(R)-PGlF p IS-ethyl-PGF IS-ethyI-PGF l5-ethyl-l5(R)-PGF IS-ethyl- 15(R)-PGF p IS-e'thyl-PGF l5-ethyl-PGF p l5-ethyl-l5(R)-PGF l5-ethyl-l5(R)-PGF p dihydro-lS-ethyl-PGF dihydro-l5-ethyl-PGF, dihydro-l5-ethyl-15(R)-PGF dihydrol S-ethyl- 15(R)-PGF 1 B and the racemic forms of each of those optically active acids, and the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those optically active and racemic acids are each oxidized to the corresponding IS-ethyI-PGE or l5-ethyl-l5(R)-PGE acid or ester.

I claim 1. An optically active compound of the formula or a racemic compound of that. formula and the mirror image thereof, wherein R is hydrogen, alkyl of one to eight carbon atoms, inclusive, or a pharmacologically acceptable cation, and wherein R is methyl or ethyl.

2. 15-Methyl-PGF p an optically active compound according to claim 1 wherein R is hydrogen and R is methyl.

3. Racemic IS-methyI-PGF p a compound according to claim 1 wherein R is hydrogen and R is methyl.

Y 2B, an optically active compound according to claim 1.

5. A compound according to claim 1 wherein R is alkyl of one to 4 carbon atoms.

6. A compound according to claim 1 wherein R is methyl.

7. 15-Methyl-PGF methyl ester, 21 compound according to'claim l.

8. 15-Ethyl-PGF methyl ester, a compound according to claim 1. 

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA
 2. 15-Methyl-PGF2 an optically active compound according to claim 1 wherein R1 is hydrogen and R2 is methyl.
 3. Racemic 15-methyl-PGF2 , a compound according to claim 1 wherein R1 is hydrogen and R2 is methyl.
 4. 15-Ethyl-PGF2 , an optically active compound according to claim
 1. 5. A compound according to claim 1 wherein R1 is alkyl of one to 4 carbon atoms.
 6. A compound according to claim 1 wherein R1 is methyl.
 7. 15-Methyl-PGF2 , methyl ester, a compound according to claim
 8. 15-Ethyl-PGF2 , methyl ester, a compound according to claim 